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Linking Clinical Parameters and Genotype in Dilated Cardiomyopathy
Circulation: Heart Failure ( IF 9.7 ) Pub Date : 2018-11-07 , DOI: 10.1161/circheartfailure.118.005459
Jared M Churko 1
Affiliation  

See Article by Verdonschot et al


Establishing an accurate diagnosis, assessing prognosis, and managing treatment are fundamental to patient care. Clinical parameters, such as left ventricular (LV) ejection fraction and LV end-diastolic diameter, are critical to initially establish a diagnosis of dilated cardiomyopathy (DCM) and hypokinetic non-DCM. These clinical parameters are also used to monitor disease progression and treatment response. However, use of sequencing/genotyping technologies within the clinic is becoming more common in the era of personalized medicine. Efforts to sequence patients and classify the impact of mutations in cardiomyopathy-associated genes are helping to identify key diagnostic subgroups.


In this issue of Circulation: Heart Failure, Verdonschot et al1 studied the association between DCM and hypokinetic non-DCM patients’ genotype with improvement in reverse remodeling of the LV in response to medical therapy. The study defined reverse remodeling of the LV as an increase in LV ejection fraction and a decrease in LV end-diastolic diameter for ≈1 year of follow-up. Patients were genotyped using a custom panel of 47 genes associated with cardiomyopathy. Over 52% of the 346 patients studied had reverse remodeling of the LV after 12 months of treatment. Pathogenic gene mutations were found in 22% of patients (n=78). The most prevalent genes involved in these patients were titin (TTN, 9.5%) followed by lamin A/C (LMNA; 2.6%).


The findings of Verdonschot et al1 confirm and enhance the published literature,2–6 indicating that disease caused by mutations in LMNA are associated with a particularly severe form of DCM, with high arrhythmic burden, progression to end-stage heart failure, and here, lower likelihood of LV recovery. In contrast, disease caused by truncation mutations in titin (TTNtv) is associated with more mild disease that seems more responsive to unloading therapy,7–9 and thus more likely to favorably remodel and recover with standard medical therapy for heart failure. Furthermore, because of the large size of titin and the presence of multiple isoforms, the location of variants within the gene also plays a role in determining DCM disease burden. TTNtv localized towards the N terminus, affecting certain TTN isoforms (N2B and N2BA), and within exons commonly removed during splicing have been associated with a more mild or no pathology,10 whereas variants located in commonly expressed exons (and thus, translated into the final protein product) are predicted to be pathogenic.9 These findings underscore that genotype can influence the clinical decision-making process and that differentiating clinically relevant subgroups of DCM, guided by genetic cause, may play an important role in diagnosis, prognosis, and management. From an academic perspective, gaining greater understanding in gene- and variant-specific mechanisms will undoubtedly lead to advances in our understanding of how protein-protein domain perturbations,11 changes in mRNA splicing,12 and protein functional changes13 contribute to in disease pathogenesis. This information will be critical to identify molecular mechanisms leading to DCM and to design targeted drug therapies to treat distinct genetic subclasses of DCM pathology.


The genetic basis of DCM/hypokinetic non-DCM also has important clinical implications. Receipt of genetic results is a reminder to think about the patient’s family in addition to the individual presenting for care in clinic.14 If there is no clear explanation for why cardiomyopathy developed, a detailed family history should be obtained, and first-degree relatives should be screened to evaluate for familial disease.15 Although the genetic cause of DCM is diverse and incompletely resolved and the yield of clinical genetic testing is currently relatively modest (a genetic cause can be detected ≈20% of the time),15,16 identifying a pathogenic mutation in a patient provides unique and valuable information to guide management of the patient and their family. At-risk relatives can be definitively identified and followed appropriately. Relatives not at risk can be reassured. Affected individuals can be given more precise prognostic forecasts, and more aggressive therapy can be steered towards those predicted to have more aggressive disease, based on genetic substrate. The work of Verdonschot et al1 highlight that adding genetic information, in addition to clinical parameters, may better predict reverse remodeling of the LV than clinical parameters alone. Linking the degree of disease burden to variants (and properly defining variants of unknown significance) is still necessary. Efforts in linking disease burden to variants will ultimately lead to improvements in patient care and in our understanding of cardiomyopathies.


None.


The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.




中文翻译:

将扩张型心肌病的临床参数与基因型联系起来

请参阅 Verdonschot 等人的文章


建立准确的诊断、评估预后和管理治疗是患者护理的基础。左心室 (LV) 射血分数和 LV 舒张末期内径等临床参数对于初步诊断扩张型心肌病 (DCM) 和运动功能减退的非 DCM 至关重要。这些临床参数还用于监测疾病进展和治疗反应。然而,在个性化医疗时代,在诊所内使用测序/基因分型技术变得越来越普遍。对患者进行测序并对心肌病相关基因突变的影响进行分类,有助于确定关键的诊断亚组。


在本期《循环:心力衰竭》中,Verdonschot 等人1研究了扩张型心肌病 (DCM) 和运动机能减退的非扩张型心肌病 (DCM) 患者的基因型与药物治疗对左室逆重塑的改善之间的关联。该研究将左室逆重塑定义为在约 1 年的随访中左室射血分数增加和左室舒张末期直径减小。使用由 47 个与心肌病相关的基因组成的定制组对患者进行基因分型。在 12 个月的治疗后,所研究的 346 名患者中超过 52% 的左室发生了逆转重塑。22% 的患者 (n=78) 发现致病基因突变。这些患者中最常见的基因是肌动蛋白(TTN,9.5%),其次是核纤层蛋白A/C(LMNA;2.6%)。


Verdonschot 等人的研究结果1证实并增强了已发表的文献,2-6表明LMNA突变引起的疾病与特别严重的 DCM 形式相关,具有高心律失常负担,进展为终末期心力衰竭,这里,左心室恢复的可能性较低。相比之下,由肌联蛋白截短突变 ( TTNtv ) 引起的疾病与更轻微的疾病相关,这些疾病似乎对卸载疗法更敏感,7-9,因此更有可能通过心力衰竭的标准药物治疗进行有利的重塑和恢复。此外,由于肌联蛋白尺寸较大且存在多种亚型,基因内变异的位置也在确定 DCM 疾病负担中发挥着作用。TTNtv定位于 N 末端,影响某些TTN亚型(N2B 和 N2BA),并且在剪接过程中通常被去除的外显子内,与更轻微或无病理学相关,10而位于常见表达的外显子中的变体(因此,翻译成最终蛋白质产物)预计具有致病性。9这些发现强调,基因型可以影响临床决策过程,并且在遗传原因的指导下区分 DCM 的临床相关亚组可能在诊断、预后和治疗中发挥重要作用。从学术角度来看,对基因和变异特异性机制的深入了解无疑将促进我们对蛋白质-蛋白质结构域扰动、mRNA 剪接的11变化12和蛋白质功能变化13如何影响疾病发病机制的理解取得进展。这些信息对于确定导致 DCM 的分子机制以及设计靶向药物疗法来治疗 DCM 病理的不同遗传亚型至关重要。


DCM/运动机能减退的非 DCM 的遗传基础也具有重要的临床意义。收到基因结果提醒我们除了在诊所接受护理的个人之外,还要考虑患者的家人。14如果没有明确解释为什么会出现心肌病,应获取详细的家族史,并对一级亲属进行筛查以评估是否有家族性疾病。15尽管 DCM 的遗传原因多种多样且尚未完全解决,而且目前临床基因检测的效果相对较小(约 20% 的时间可以检测到遗传原因),15,16 识别患者的致病性突变提供了独特的方法。以及指导患者及其家人的管理的宝贵信息。可以明确识别高危亲属并进行适当跟踪。没有处于危险中的亲属可以放心。可以对受影响的个体进行更精确的预后预测,并且可以根据遗传底物对那些预测患有更严重疾病的人进行更积极的治疗。Verdonschot 等人的工作1强调,除了临床参数之外,添加遗传信息可能比单独的临床参数更好地预测左心室的逆重塑。将疾病负担程度与变异联系起来(并正确定义意义不明的变异)仍然是必要的。将疾病负担与变异联系起来的努力最终将改善患者护理和我们对心肌病的理解。


没有任何。


本文表达的观点不一定代表编辑或美国心脏协会的观点。


更新日期:2018-11-07
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